tbuckley/cabot-search huggingface dataset:
Porphyromonas gingivalis, a periodontal pathogen, impairs post-infarcted myocardium by inhibiting autophagosome–lysosome fusion
Authors: Yuka Shiheido-Watanabe, Yasuhiro Maejima, Shun Nakagama, Qintao Fan, Natsuko Tamura, Tetsuo Sasano
Journal: International Journal of Oral Science (2023)

Abstract While several previous studies have indicated the link between periodontal disease (PD) and myocardial infarction (MI), the underlying mechanisms remain unclear. Autophagy, a cellular quality control process that is activated in several diseases, including heart failure, can be suppressed by Porphyromonas gingivalis ( P.g .). However, it is uncertain whether autophagy impairment by periodontal pathogens stimulates the development of cardiac dysfunction after MI. Thus, this study aimed to investigate the relationship between PD and the development of MI while focusing on the role of autophagy. Neonatal rat cardiomyocytes (NRCMs) and MI model mice were inoculated with wild-type P.g . or gingipain-deficient P.g . to assess the effect of autophagy inhibition by P.g . Wild-type P.g .-inoculated NRCMs had lower cell viability than those inoculated with gingipain-deficient P.g . This study also revealed that gingipains can cleave vesicle-associated membrane protein 8 (VAMP8), a protein involved in lysosomal sensitive factor attachment protein receptors (SNAREs), at the 47th lysine residue, thereby inhibiting autophagy. Wild-type P.g .-inoculated MI model mice were more susceptible to cardiac rupture, with lower survival rates and autophagy activity than gingipain-deficient P.g .-inoculated MI model mice. After inoculating genetically modified MI model mice (VAMP8-K47A) with wild-type P.g ., they exhibited significantly increased autophagy activation compared with the MI model mice inoculated with wild-type P.g ., which suppressed cardiac rupture and enhanced overall survival rates. These findings suggest that gingipains, which are virulence factors of P.g ., impair the infarcted myocardium by cleaving VAMP8 and disrupting autophagy. This study confirms the strong association between PD and MI and provides new insights into the potential role of autophagy in this relationship.
Genomic epidemiology of syphilis in England: a population-based study
Authors: Mathew A Beale, Louise Thorn, Michelle J Cole, Rachel Pitt, Hannah Charles, Michael Ewens, Patrick French, Malcolm Guiver, Emma E Page, Erasmus Smit, Jaime H Vera, Katy Sinka, Gwenda Hughes, Michael Marks, Helen Fifer, Nicholas R Thomson
Journal: The Lancet Microbe (2023)

Syphilis is a sexually transmitted bacterial infection caused by Treponema pallidum subspecies pallidum. Since 2012, syphilis rates have risen dramatically in many high-income countries, including England. Although this increase in syphilis prevalence is known to be associated with high-risk sexual activity in gay, bisexual, and other men who have sex with men (GBMSM), cases are rising in heterosexual men and women. The transmission dynamics within and between sexual networks of GBMSM and heterosexual people are not well understood. We aimed to investigate if whole genome sequencing could be used to supplement or enhance epidemiological insights around syphilis transmission.
Diffuse Pleural Mesothelioma: Advances in Molecular Pathogenesis, Diagnosis, and Treatment
Authors: Christopher A. Febres-Aldana, Rachel Fanaroff, Michael Offin, Marjorie G. Zauderer, Jennifer L. Sauter, Soo-Ryum Yang, Marc Ladanyi
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.
Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy
Authors: Francis A. Lévi, Alper Okyar, Eva Hadadi, Pasquale F. Innominato, Annabelle Ballesta
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.
Deciphering Drug Targets and Actions with Single-Cell and Spatial Resolution
Authors: Zhengyuan Pang, Benjamin F. Cravatt, Li Ye
Journal: The Annual Review of Pharmacology and Toxicology (2023)

Recent advances in chemical, molecular, and genetic approaches have provided us with an unprecedented capacity to identify drug-target interactions across the whole proteome and genome. Meanwhile, rapid developments of single-cell and spatial omics technologies are revolutionizing our understanding of the molecular architecture of biological systems. However, a significant gap remains in how we align our understanding of drug actions, traditionally based on molecular affinities, with the in vivo cellular and spatial tissue heterogeneity revealed by these newer techniques. Here, we review state-of-the-art methods for profiling drug-target interactions and emerging multiomics tools to delineate the tissue heterogeneity at single-cell resolution. Highlighting the recent technical advances enabling high-resolution, multiplexable in situ small-molecule drug imaging (clearing-assisted tissue click chemistry, or CATCH), we foresee the integration of single-cell and spatial omics platforms, data, and concepts into the future framework of defining and understanding in vivo drug-target interactions and mechanisms of actions.
Dynamic Multiplex Tissue Imaging in Inflammation Research
Authors: Stefan Uderhardt, Georgiana Neag, Ronald N. Germain
Journal: Annual Review of Pathology Mechanisms of Disease (2023)

Inflammation is a highly dynamic process with immune cells that continuously interact with each other and parenchymal components as they migrate through tissue. The dynamic cellular responses and interaction patterns are a function of the complex tissue environment that cannot be fully reconstructed ex vivo, making it necessary to assess cell dynamics and changing spatial patterning in vivo. These dynamics often play out deep within tissues, requiring the optical focus to be placed far below the surface of an opaque organ. With the emergence of commercially available two-photon excitation lasers that can be combined with existing imaging systems, new avenues for imaging deep tissues over long periods of time have become available. We discuss a selected subset of studies illustrating how two-photon microscopy (2PM) has helped to relate the dynamics of immune cells to their in situ function and to understand the molecular patterns that govern their behavior in vivo. We also review some key practical aspects of 2PM methods and point out issues that can confound the results, so that readers can better evaluate the reliability of conclusions drawn using this technology.
NIR‐II Regulation of Mitochondrial Potassium Channel with Dual‐Targeted Conjugated Oligomer Nanoparticles for Efficient Cancer Theranostics In Vivo
Authors: Chaoqun Li, Dong Gao, Yijian Gao, Ran Zhang, Xiongwei Qu, Shengliang Li, Chengfen Xing
Journal: Advanced Healthcare Materials (2023)

Cell fate can be efficiently modulated by switching ion channels. However, the precise regulation of ion channels in cells, especially in specific organelles, remains challenging. Herein, biomimetic second near-infrared (NIR-II) responsive conjugated oligomer nanoparticles with dual-targeted properties are designed and prepared to modulate the ion channels of mitochondria to selectively kill malignant cells in vivo. Upon 1060 nm laser irradiation, the mitochondria-located nanoparticles photothermally release a specific ion inhibitor of the potassium channel via a temperature-sensitive liposome, thus altering the redox balance and pathways of mitochondria. NIR-II responsive nanoparticles can effectively regulate the potassium channels of mitochondria and fully suppress tumor growth. This work provides a new modality based on the NIR-II nanoplatform to regulate ion channels in specific organelles and proposes an effective therapeutic mechanism for malignant tumors.
Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases
Authors: Ekaterini Tiligada, Daria Gafarov, Maria Zaimi, Joana Vitte, Francesca Levi-Schaffer
Journal: The Annual Review of Pharmacology and Toxicology (2023)

The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.
Treatments for COVID-19
Authors: Hayden S. Andrews, Jonathan D. Herman, Rajesh T. Gandhi
Journal: Annual Review of Medicine (2023)

The treatment for COVID-19 has evolved rapidly since the start of the pandemic and now consists mainly of antiviral and immunomodulatory agents. Antivirals, such as remdesivir and nirmatrelvir-ritonavir, have proved to be most useful earlier in illness (e.g., as outpatient therapy) and for less severe disease. Immunomodulatory therapies, such as dexamethasone and interleukin-6 or Janus kinase inhibitors, are most useful in severe disease or critical illness. The role of anti-SARS-CoV-2 monoclonal antibodies has diminished because of the emergence of viral variants that are not anticipated to be susceptible to these treatments, and there still is not a consensus on the use of convalescent plasma. COVID-19 has been associated with increased rates of venous thromboembolism, but the role of antithrombotic therapy is limited. Multiple investigational agents continue to be studied, which will alter current treatment paradigms as new data are released.
High-Sensitivity Cardiac Troponin Assays: Ready for Prime Time!
Authors: Konstantin A. Krychtiuk, L. Kristin Newby
Journal: Annual Review of Medicine (2023)

Rapid and accurate triage of patients presenting with chest pain to an emergency department (ED) is critical to prevent ED overcrowding and unnecessary resource use in individuals at low risk of acute myocardial infarction (AMI) and to efficiently and effectively guide patients at high risk to definite therapy. The use of biomarkers for rule-out or rule-in of suspected AMI has evolved substantially over the last several decades. Previously well-established biomarkers have been replaced by cardiac troponin (cTn). High-sensitivity cTn (hs-cTn) assays represent the newest generation of cTn assays and offer tremendous advantages, including improved sensitivity and precision. Still, implementation of these assays in the United States lags behind several other areas of the world. Within this educational review, we discuss the evolution of biomarker testing for detection of myocardial injury, address the specifics of hs-cTn assays and their recommended use within triage algorithms, and highlight potential challenges in their use. Ultimately, we focus on implementation strategies for hs-cTn assays, as they are now clearly ready for prime time. Expected final online publication date for the Annual Review of Medicine, Volume 75 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Hemosuccus Pancreaticus Caused by Splenic Artery Pseudoaneurysm: Two Cases Diagnosed and Treated With EUS
Authors: Mehdi Mohamadnejad, Ali Ali Asgari, Mohammad Al-Haddad
Journal: Clinical Gastroenterology and Hepatology (2023)

Here we present 2 cases of hemosuccus pancreaticus caused by splenic artery pseudoaneurysm (SAPA) diagnosed and treated with endoscopic ultrasound (EUS). A 15-year-old boy presented with intermittent attacks of severe abdominal pain associated with hematemesis for 4 months ago. He reported a history of blunt abdominal trauma 2 years before the presentation. The source of bleeding was not identified despite several endoscopic examinations, and computed tomography (CT) angiography. Upper gastrointestinal (GI) endoscopy revealed fresh blood in the duodenum raising concern for a pancreatobiliary source of bleeding. On EUS, fresh blood was noted to be seeping from the major papilla (Figure A). EUS revealed a small SAPA measuring 8 × 6 mm (Figure B). Blood flow was observed entering pancreatic duct from the pseudoaneurysm on Doppler examination (Figure C). A 0.5 mL of cyanoacrylate glue followed by 1 mL of distilled water were injected into the SAPA through a 22-gauge fine-needle aspiration needle. During injection, small spillage of glue to the pancreatic duct was observed (Video 1). At 6-month follow-up, the patient remained clinically well with no recurrence of GI bleeding or abdominal pain. An 87-year-old woman with a past history of acute pancreatitis developed GI bleeding caused by SAPA noted on CT scan, and was treated with percutaneous coil embolization. Nine months later, she presented with recurrent GI bleeding. CT angiography revealed the previously treated pseudoaneurysm with no arterial enhancement; but a small branch of the splenic artery was observed near the previously coiled SAPA (Video 1). EUS revealed a pseudoaneurysm measuring 30 × 16 mm with active arterial blood flow on Doppler originating from a branch of splenic artery (Figure D). A 2.5 mL of cyanoacrylate followed by 2 mL of distilled water were injected using a 22-gauge fine-needle aspiration needle, and the blood flow stopped. Subsequent CT angiography revealed a partial splenic infarction that was asymptomatic (Video 1). The patient remained clinically well with no recurrence of bleeding after 3 months of follow-up. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI3YTVjOGQzYThkMWM4MTc5NTA5ZTZiMzU5NDQ3ODBjOSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzE1NDY2NzE5fQ.SvVkdOAEHUn3532cxWEOezp4OnhFP9t08uxnZZCfZdkTX2q3DiPUPJVXeOyi1bWy-irQ9IAg9HXbezLvE-W5TGk16YJJdwIBm6dUoWYzIBWiwtW5wF-MJehu_WNwoKB93xWQqNqEhckBCrEXPvvTwUlwmrDZvY5u_z1EQJVv7ZeVxgYxPq_Uesf5RX9TgW2gVdRHQ2codk_EvDywA8xgbvPUM7CW53lig6OPwiQHrvEi_rLSpeVuMZ8_oOzRYXtRAhfWpaGyBDtr5RjCmaZgSdAR06HpwLxrkENBLHSOp5lNXY4GK60RhWkh70B2bQOlZPYSJnmGp4-OP99I8Cg27Q Download .mp4 (72.93 MB) Help with .mp4 files Video
Checkpoint inhibitor antibody type influences the development of cutaneous immune-related adverse events: A multi-institutional study
Authors: Katie Roster, Ahmad Rajeh, Nga Nguyen, Kimberly Tang, Shijia Zhang, Hannah Rashdan, Guihong Wan, Bonnie W. Leung, Sara Khattab, Steven Chen, Nicole R. LeBoeuf, Yevgeniy R. Semenov
Journal: Journal of the American Academy of Dermatology (2023)
Cu–Sr Bilayer Bioactive Glass Nanoparticles/Polydopamine Functionalized Polyetheretherketone Enhances Osteogenic Activity and Prevents Implant‐Associated Infections through Spatiotemporal Immunomodulation
Authors: Yuezhou Wu, Shicheng Huo, Shu Liu, Qimin Hong, You Wang, Zhuocheng Lyu
Journal: Advanced Healthcare Materials (2023)

Key factors contributing to implantation failures include implant-associated infections (IAIs) and insufficient osseointegration of the implants. Polyetheretherketone (PEEK) is widely used in orthopedics, yet its clinical applications are restricted due to its poor osteogenic and antibacterial properties as well as inadequate immune responses. To overcome these drawbacks, a novel spatiotemporal immunomodulation approach is proposed, chelating Cu-Sr bilayer bioactive glass nanoparticles (CS-BGNs) onto the PEEK surface via polydopamine (PDA). The CS-BGNs possess a bilayer core-shell structure where copper is distributed in the outer layer and strontium is clustered in the inner layer. The results show that CS-BGNs/PDA functionalized PEEK demonstrates a controlled and sequential release of Cu
Control of cell penetration enhancer shielding and endosomal escape-kinetics crucial for efficient and biocompatible siRNA delivery
Authors: Alessio Malfanti, Haider Sami, Anna Balasso, Giulia Marostica, Busra Arpac, Francesca Mastrotto, Giuseppe Mantovani, Elisa Cola, Martina Anton, Paolo Caliceti, Manfred Ogris, Stefano Salmaso
Journal: Journal of Controlled Release (2023)

Although cationic liposomes are efficient carriers for nucleic acid delivery, their toxicity often hampers the clinical translation. Polyethylene glycol (PEG) coating has been largely used to improve their stability and reduce toxicity. Nevertheless, it has been found to decrease the transfection process. In order to exploit the advantages of cationic liposomes and PEG decoration for nucleic acid delivery, liposomes decorated with tetraArg-[G-1]-distearoyl glycerol (Arg4-DAG) dendronic oligo-cationic lipid enhancer (OCE) and PEG-lipid have been investigated. Non decorated or OCE-decorated lipoplexes (OCEfree-LPX and OCE-LPX, respectively) were obtained by lipid film hydration using oligonucleotide (ON) solutions. PEG and OCE/PEG decorated lipoplexes (PEG-OCEfree-LPX and PEG-OCE-LPX, respectively) were obtained by post-insertion of 2 or 5 kDa PEG-DSPE on preformed lipoplexes. The OCE decoration yielded lipoplexes with size of about 240 nm, 84% loading efficiency at 10 N/P ratio, ten times higher than OCEfree-LPX, and prevented the ON release when incubated with physiological heparin concentration or with plasma. The PEG decoration reduced the zeta potential, enhanced the lipoplex stability in serum and decreased both hemolysis and cytotoxicity, while it did not affect the lipoplex size and ON loading. With respect to OCEfree-LPX, the OCE-LPX remarkably associated with cells and were taken up by different cancer cell lines (HeLa and MDA-MB-231). Interestingly, 2 or 5 kDa PEG decoration did not reduce either the cell interaction or the cell up-take of the cationic lipoplexes. With siRNA as a payload, OCE enabled efficient internalization, but endosomal release was hampered. Post-transfection treatment with the lysosomotropic drug chloroquine allowed to identify the optimal time point for endosomal escape. Chloroquine treatment after 12 to 20 h of LPX pre-incubation enabled siRNA mediated target knockdown indicating that this is the time window of endo-lysosomal processing. This indicates that OCE can protect siRNA from lysosomal degradation for up to 20 h, as shown by these rescue experiments.
Controlled extracellular vesicles release from aminoguanidine nanoparticle-loaded polylysine hydrogel for synergistic treatment of spinal cord injury
Authors: Shaoke Wang, Rui Wang, Jiangjie Chen, Biao Yang, Jiawei Shu, Feng Cheng, Yiqing Tao, Kesi Shi, Chenggui Wang, Jingkai Wang, Kaishun Xia, Yuang Zhang, Qixin Chen, Chengzhen Liang, Jianbin Tang, Fangcai Li
Journal: Journal of Controlled Release (2023)
In-class transition (iCT) of proteasome inhibitor-based therapy: a community approach to multiple myeloma management
Authors: Robert M. Rifkin, Saulius K. Girnius, Stephen J. Noga, Ruemu E. Birhiray, Suman Kambhampati, Sudhir Manda, Roger M. Lyons, Habte A. Yimer, Dasha Cherepanov, Eric Lloyd, Presley Whidden, Joshua Richter
Journal: Blood Cancer Journal (2023)

Abstract Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61–78). ORR increased from 62% at the end of induction to 80% following in- class transition ( i CT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. i CT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.
Normal values for native T1 at 1.5 T in the pericardial fluid of healthy volunteers
Authors: Simon Thalén, Joao G Ramos, Henrik Engblom, Andreas Sigfridsson, Peder Sörensson, Martin Ugander
Journal:  (2023)

Abstract Aims T1 mapping cardiovascular magnetic resonance (CMR) imaging has been used to characterize pericardial effusions. The aim of this study was to measure pericardial fluid native T1 values in healthy volunteers to establish normal values. Methods and results Prospectively recruited volunteers (n = 30) underwent CMR at 1.5 T, and native T1 maps were acquired using a modified look-locker inversion recovery 5s(3s)3s acquisition scheme. A volume of pericardial fluid was imaged in a short-axis slice and in a slice perpendicular to the short-axis orientation. A reliable measurement had a region of interest (ROI) size &amp;gt; 10 mm2, coefficient of variation &amp;lt; 10%, and a relative difference &amp;lt; 5% between the two slice orientations. In 26/30 (87%) of volunteers, there was a sufficient amount of pericardial fluid to enable reliable measurement. Native T1 of pericardial fluid was 3262 ± 163 (95% normal limits 2943–3581 ms) and did not differ in the perpendicular slice orientation (3267 ± 173 ms, P = 0.75), due to sex (female 3311 ± 177 vs. male 3220 ± 142 ms, P = 0.17), age (R2 = 0.03, P = 0.44), heart rate (R2 = 0.005, P = 0.7), or size of the ROI (0.06, P = 0.23). Conclusion This study shows that T1 values can be reliably measured in the pericardial fluid of healthy volunteers. It is the first to report normal reference ranges for T1 values at 1.5 T in the pericardial fluid of healthy volunteers.